Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection.

Abstract

BACKGROUND:

Mutations in either Aβ Precursor protein (APP) or genes that regulate APP processing, such as BRI2/ITM2B and PSEN1/PSEN2, cause familial dementias. Although dementias due to APP/PSEN1/PSEN2 mutations are classified as familial Alzheimer disease (FAD) and those due to mutations in BRI2/ITM2B as British and Danish dementias (FBD, FDD), data suggest that these diseases have a common pathogenesis involving toxic APP metabolites. It was previously shown that FAD mutations in APP and PSENs promote activation of caspases leading to the hypothesis that aberrant caspase activation could participate in AD pathogenesis.

RESULTS:

Here, we tested whether a similar mechanism applies to the Danish BRI2/ITM2B mutation. We have generated a genetically congruous mouse model of FDD, called FDD(KI), which presents memory and synaptic plasticity deficits. We found that caspase-9 is activated in hippocampal synaptic fractions of FDD(KI) mice and inhibition of caspase-9 activity rescues both synaptic plasticity and memory deficits.

CONCLUSION:

These data directly implicate caspase-9 in the pathogenesis of Danish dementia and suggest that reducing caspase-9 activity is a valid therapeutic approach to treating human dementias.

• Authors: Robert Tamayev, Nsikan Akpan, Ottavio Arancio, Carol M Troy, Luciano D'Adamio
• Journal: Molecular neurodegeneration (Mol Neurodegener) Vol. 7 Pg. 60 (Dec 10 2012) ISSN: 1750-1326 [Electronic] England
• PMID: 23217200 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Caspase 9

Topics

• Alzheimer Disease (enzymology, genetics)
• Animals
• Blotting, Western
• Caspase 9 (metabolism)
• Cataract (enzymology, genetics)
• Cerebellar Ataxia (enzymology, genetics)
• Deafness (enzymology, genetics)
• Dementia (enzymology, genetics)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Gene Knock-In Techniques
• Memory (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Neuronal Plasticity (drug effects, physiology)
• Organ Culture Techniques
• Patch-Clamp Techniques